Transcript G-protein coupled receptor

Pharmacodynamics
How drugs act: Molecular
aspects
Pawitra Pulbutr
B.Pharm (Hon),
M.Sc. In Pharm (Pharmacology)
Objectives
อธิบายถึงเป้ าหมายที่ยาออกฤทธิ์ท่สี าคัญได้
อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Receptor ชนิ ด Channellinked receptor, G-protein receptor,
Kinase-linked receptor และ Receptor that
regulate gene transcription รวมทัง้ ความแตกต่างของการ
ออกฤทธิ์ผ่านReceptors แต่ละชนิ ดได้
อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Ion channel
อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Enzymes
อธิบายถึงกลไกการออกฤทธิ์ของยาผ่าน Carrier molecules
Target for drug action
Protein
• Receptors
• Ion channels
• Enzymes
• Carrier molecules
Other :Tubulin,
DNA, RNA
Chemotherapy >>>
Anticancer, Antimicrobial
Receptors
ตัวรับสัญญาณของเซลล์
การสือ่ สารกันระหว่างเซลล์
เซลล์ทางานได้
สอดคล้องกัน
สาร = Chemical messenger…
neurotransmitters, hormones,
cytokines, growth factors
Chemical
messenger
Receptor
Ligand
• Chemical messenger
• Drug (Agonist or Antagonist)
Receptor
Signal
transduction
Physiological response
Drugs act at receptor
Agonist
Antagonist
Receptor
activation
Block receptor
Physiological
response
No
activation
No Physiological
response
Drugs act at receptor
Receptor of chemical messenger
in the body
Receptor
Receptor of specific
drug
Receptors are mostly named after their ligand.
Receptor classification by their localization
• Cell membrane receptor
• Nuclear receptor or intracellular receptor
Kinase linked receptor
Channel linked
receptor
(Ionotropic receptor)
Receptor families
Receptor that
regulate gene
transcription
G-protein coupled
receptor
(Metabotropic
receptor, 7transmembrane
receptor)
Figure 2.1 Types of receptor-effector linkage
Channel linked receptor
• Nicotinic
receptor…prototype
ACh …natural ligand
5 •subunits
Ligand binding
2  + 1 + 1 + 1 
Channel
lining
One
subunit
One receptor
G-protein coupled receptor
(GPCR)
o Cell membrane receptor
o Single polypeptide chain
o Muscarinic receptor
o Adrenergic receptor
o Dopamine receptor
o 5-HT receptor
o Opiate receptor
o GPCR >>> Major drug target
G-protein
coupled
receptor
Comprised of…..
Single
peptide
1. Extracellular N-terminal
2. 7-Transmembrane alpha
helices
• ligand
3. Intracellular C-terminal
• Linked with
“G-protein”
binding
Role of G-protein
G protein
“free”
GTPase
Effector
molecule
Second messenger
production
Effector molecule or target protein
1. Membrane enzyme
• Adenylate cyclase
• Phospholipase C
2. Ion channels
Ligand
G-protein coupled receptor
Active G protein ( GTP)
Enzyme
Adenylate
cyclase
Phospholipase C
IP3
cAMP
cAMP dep. Protein kinase
phosphorylate
enzyme
Ion channel
Ion channel
DAG
Open channel
Increase
intracellular
calcium
Activate
protein
kinase C
Tyrosine kinase receptor/ Guanylate
cyclase linked receptor
Tyrosine kinase receptor
• Insulin receptor
• Cytokine receptor ***
• Growth factor receptor
***
Guanylate cyclase linked receptor
• Atrial natriuretic peptide receptor
Kinase linked receptor
1. Extracellular domain
Ligand binding
2. Transmembrane region
Single helix
3. Intracellular domain
Catalytic domain
(Enzyme activity)
Ras = membrane
protein
Ras/ Raf pathway
Jak/ Stat pathway
Jak = cytosolic
Tyrosine kinase
Stat = transcriptional
factor
Receptor that regulate gene
transcription
• Intracellular receptor (Nuclear receptor)
• Lipophilic ligand
• Steroid receptor, Thyroid receptor,
• Vitamin A receptor, Vitamin D receptor
Receptor Structure
1. DNA binding
domain
2. Ligand binding
domain
3. Transcription
control domain
Zinc finger
Bind with DNA
at response
element
Peroxisome Proliferator Activated
Receptor (PPARs)
• Nuclear receptor
• PPAR alpha, PPAR beta, PPAR gamma
Figure 2.1 Types of receptor-effector linkage
Receptor dynamics
Prolonged agonist activation
Desensitization
• Decrease response (decrease sensitivity)
• fast occur
• Phosphorylation of RC >>> Steric hindrance
Receptor down regulation
• Decrease number of receptor
• slow occur… receptor internalization
Decrease Response
Tolerance
Receptor upregulation
Prolonged antagonist blockade
• Increase number of receptor
Over Response
•-blocker (-adrenergic receptor antagonist)
•May induce RC upregulation
•If sudden stop >>> Over response >>> hypertension
•Should be slowly stop the drugs
Ion channels
Drugs which directly acting at ion channels
1. Block ion channels
• Physical properties
• Local anesthetics
•Block sodium channels
See table 2.2
2. Bind with accessory site on ion channel
• Dihydropyridine
Calcium channel blocker
• Benzodiazepine
Chloride channel opening
See table 2.2
Enzymes
1. Enzyme inhibitor
• Substrate analog
• Reversible
• Irreversible
2. False substrate
• Substrate analog
• Abnormal products
See table 2.3
Carrier molecules
Carrier molecules
1. Inhibitors
•
Inhibit carrier molecule function
2. False substrates
• False uptake
See table 2.4
Target for drug action
Protein
• Receptors
• Ion channels
• Enzymes
• Carrier molecules
Other :Tubulin,
DNA, RNA
Chemotherapy >>>
Anticancer, Antimicrobial
A, B, C, D, F